Gastric cancer‐derived exosomes facilitate pulmonary metastasis by activating ERK‐mediated immunosuppressive macrophage polarization

Abstract Gastric cancer (GC) with pulmonary metastasis is one of the deadliest diseases in the world; however, the underlying pathological mechanisms and potential therapeutic targets remain to be elucidated. As exosomes play indispensable roles in the formation of premetastatic niches (PMN) and cancer metastasis. Therefore, investigating the underlying mechanisms of exosome‐mediated pulmonary metastasis of GC may shed new light on identifying novel therapeutic targets for GC treatment. GC‐derived exosomes were isolated from the conditioned medium of mouse forestomach carcinoma (MFC) cell line. The effects of MFC‐derived exosomes on pulmonary macrophage polarization were analyzed by reverse‐ transcription polymerase chain reaction and flow cytometry. Expression of PD‐L1 and other proteins was evaluated by Western blot. Exosomal microRNAs (miRNAs) were analyzed by microarray. GC‐derived exosomes (GC‐exo) accumulated in high numbers in the lungs and were ingested by macrophages. The extracellular‐signal‐regulated kinase (ERK) signaling pathway was activated by GC‐exo, inducing macrophage immunosuppressive‐phenotype differentiation and increased PD‐L1 expression. miRNA‐sequencing identified 130 enriched miRNAs in GC‐exo. Among the enriched miRNAs, miR‐92a‐3p plays a major role in activating ERK signaling via inhibition of PTEN expression. In addition, inhibiting ERK signaling with PD98059 significantly reduced the expression of PD‐L1 in macrophages and, therefore, reversed the immunosuppressive PMN and inhibited the colonization of GC cells in the lungs. This study identified a novel mechanism of GC‐exo mediated PD‐L1 expression in lung macrophages that facilitates lung PMN formation and GC pulmonary metastasis, which also provided a potential therapeutic target for GC with pulmonary metastasis treatment.